Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria.
Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria.
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DOI：
10.3324/haematol.2019.236877
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发表时间：
2021-01-01
期刊：
影响因子：
10.1
通讯作者：
Schrezenmeier H
中科院分区：
文献类型：
--
作者：
Brodsky RA;Peffault de Latour R;Rottinghaus ST;Röth A;Risitano AM;Weitz IC;Hillmen P;Maciejewski JP;Szer J;Lee JW;Kulasekararaj AG;Volles L;Damokosh AI;Ortiz S;Shafner L;Liu P;Hill A;Schrezenmeier H
依库珠单抗是阵发性睡眠性血红蛋白尿症（PNH）的一线治疗;然而，大约11-27%的患者在接受批准剂量的依库珠单抗治疗时可能发生突破性溶血（BTH）。Ravulizumab是一种新型长效C5抑制剂，其平均半衰期是依库珠单抗的4倍，在8周给药间隔内提供立即、完全和持续的C5抑制。在两项III期研究中，在BTH终点方面，ravulizumab非劣效于依库珠单抗（Pinf ≤0.0004）;两项研究中，ravulizumab组发生BTH的患者少于依库珠单抗组（301例[补体抑制剂初治患者]，4.0% vs. 10.7%; 302例[基线时依库珠单抗稳定的患者]，0% vs. 5.1%）。在当前的分析中，对患者水平的数据进行了评价，以评估在Ravulizumab III期PNH研究的26周治疗期间报告的BTH事件相关的原因和临床参数。在所有研究中，在接受Ravulizumab治疗的患者中发生的5起BTH事件中，无1起与C5抑制不佳（游离C5 ≥0.5 mg/mL）存在时间相关性; 4起（80%）与补体扩增条件（CAC）存在时间相关性。在依库珠单抗治疗患者中发生的22起事件中，11起事件与C5抑制欠佳存在时间相关性，包括3起事件也与伴随感染相关。6例事件仅与CAC相关。5起事件与游离C5升高或报告的CAC无关。这些结果表明，通过基于体重的ravulizumab给药实现的立即、完全和持续的C5抑制通过消除PNH患者中与次优C5抑制相关的BTH来降低BTH的风险。（在clinicaltrials.gov注册标识符：研究301，NCT 02946463;研究302，NCT 03056040。）
Eculizumab is first-line treatment for paroxysmal nocturnal hemoglobinuria (PNH); however, approximately 11-27% of patients may experience breakthrough hemolysis (BTH) on approved doses of eculizumab. Ravulizumab, a new long-acting C5 inhibitor with a four times longer mean half-life than eculizumab, provides immediate, complete, and sustained C5 inhibition over 8-week dosing intervals. In two phase III studies, ravulizumab was non-inferior to eculizumab (Pinf ≤0.0004) for the BTH endpoint; fewer patients experienced BTH with ravulizumab versus eculizumab in both studies (301 [complement inhibitor−naïve patients], 4.0% vs. 10.7%; 302 [patients stabilized on eculizumab at baseline], 0% vs. 5.1%). In the current analysis, patientlevel data were evaluated to assess causes and clinical parameters associated with incidents of BTH reported during the 26-week treatment periods in the ravulizumab phase III PNH studies. Of the five BTH events occurring in ravulizumab-treated patients across the studies, none were temporally associated with suboptimal C5 inhibition (free C5 ≥0.5 mg/mL); four (80%) were temporally associated with complement-amplifying conditions (CAC). Of the 22 events occurring in eculizumab-treated patients, 11 were temporally associated with suboptimal C5 inhibition, including three events also associated with concomitant infection. Six events were associated with CAC only. Five events were unrelated to free C5 elevation or reported CAC. These results suggest that the immediate, complete, and sustained C5 inhibition achieved through weight-based dosing of ravulizumab reduces the risk of BTH by eliminating BTH associated with suboptimal C5 inhibition in patients with PNH. (Registered at clinicaltrials.gov identifiers: Study 301, NCT02946463; Study 302, NCT03056040.)
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DOI：
10.1038/nrdp.2017.28
发表时间：
2017-05-18
期刊：
Nature reviews. Disease primers
影响因子：
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作者：
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通讯作者：
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影响因子：
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